Abstract Background C3-glomerulopathy (C3G) is a rare pediatric kidney disease characterised by dysregulation of the alternative complement pathway, with glomerular deposition of C3. C3G may often present as a steroid-resistant nephrotic syndrome (SRNS), and there is no established effective therapy: the usual treatment involves corticosteroids and immunosuppressive drugs. Pioglitazone, a PPAR-γ agonist with a protective action on podocytes, was reported in a few cases as helpful in reducing proteinuria when combined with steroids. Case-Diagnosis/Treatment We report the case of a 13-year-old girl with silent past medical history who presented with SRNS. A kidney biopsy showed findings indicative of C3G. A low sodium diet and angiotensin-converting enzyme inhibitor were started; immunosuppressive treatment with mycophenolate mofetil (MMF) was administered due to the cortico-resistance. Because of poor response to the immunosuppressant, a trial with eculizumab was attempted without significant response and persistence of proteinuria in the nephrotic range. A further therapeutic trial was performed with tacrolimus with no disease remission. Due to a severe deterioration in her condition, the girl was hospitalized and treated with high-dose steroid bolus. A daily dose of oral prednisone and MMF were re-started without benefit with persistent levels of nephrotic range proteinuria. The administration of pioglitazone consistently lowered proteinuria levels for the first time since the onset of the disease, with a maintenance of the effect and normalization (< 0.15 g/24 h) at the 10-month follow-up. Conclusions In this patient affected by C3G, pioglitazone proved effective in reducing proteinuria levels.